Pravastatin, having the chemical designation [1S-[1α(βS*,δS*),2α,6α,8β-(R*),8aα]]-1,2,6,7,8,8a-Hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid, was originally disclosed by Terahara et al. in U.S. Pat. No. 4,346,227. This compound, typically included as a sodium salt in pharmaceutical formulations, is known to function as a lipid-lowering compound. In a commonly accepted mechanism of action, pravastatin inhibits cholesterol biosynthesis by inhibiting HMG-CoA reductase, an enzyme that catalyzes an early rate-limiting step in cholesterol biosynthesis, i.e., the conversion of HMG-CoA to mevalonate. This inhibition, and resulting reduction, in cholesterol levels in humans is desirable, particularly in those individuals having hyperlipidemia, or those having experienced, or who are believed to be susceptible to experiencing, coronary or cardiovascular events.
Pravastatin sodium is marketed in the form of tablets for oral administration in 10 mg, 20 mg, 40 mg and 80 mg strengths. These tablets are currently indicated in the prevention of coronary events, (b) the secondary prevention of cardiovascular events; and (c) hyperlipidemia.
One property affecting the formulation of pravastatin is its tendency to become unstable and degrade, forming lactone as a degradation product, upon exposure to certain environmental conditions (e.g., acidic environments) or pharmaceutical excipients. Despite precautions, pravastatin degradation is so prevalent that the shelf life of current pravastatin formulations is limited at present to 3 years from the date of manufacture.
Prior efforts to limit pravastatin degradation in pharmaceutical formulations involved providing a formulation with a highly alkaline pH, i.e., greater than 9. This was accomplished by including basic components (e.g., buffering agents) in the formulations in amounts effective to provide the formulation with the desired alkaline pH. Illustrative of these basic components include magnesium oxide, aluminum oxide, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide. Commonly, these components constitute up to about 75 wt. % of the oral dosage form.
However, formulations having this relatively high pH are potentially harmful to the gastric mucosa of patients. Further, the inclusion of certain binders, fillers, disintegrants, lubricants, coloring agents, and other commonly used excipients was found to cause the pravastatin to become unstable and degrade, even when the formulation was prepared to exhibit a highly alkaline pH (i.e., a pH in excess of 9).
Other efforts to limit pravastatin degradation in oral pharmaceutical formulations required processing of the pravastatin prior to preparing the finished formulation. These processes included co-crystallization and/or co-precipitation of the pravastatin with a basifying agent to form a finely distributed homogenous component. Processes of this type, however, are costly, and also require the use of organic solvents that may pose hazards to workers during processing, and which must be removed from the finished formulation.
Thus, despite prior efforts, there remains a need for oral pravastatin formulations, and processes for their preparation and use, that have a relatively neutral pH, in which the pravastatin remains substantially stable, and that do not require processing that is relatively costly, unduly complicated, or use potentially hazardous organic solvents in the preparation of the formulations.
The present invention meets the aforesaid and other needs, as will be apparent from the description of the invention provided herein.